tbuckley/cabot-search huggingface dataset:
Body mass index and overall survival in multiple myeloma.
Authors: Bei Wang, Benjamin Avi Derman, Spencer Langerman, Elizabeth Stepniak, Julie Johnson, Wei Zhang, Andrzej J. Jakubowiak, Brian C Chiu
Journal: Journal of Clinical Oncology (2022)

e20007 Background: Elevated body mass index (BMI) is associated with a higher risk of multiple myeloma (MM), but its influence on survival is unclear. Studies evaluating BMI and mortality of MM have reported conflicting findings and most have limited data on clinical prognostic factors. We evaluated the associations between BMI at different life stages up to the time of diagnosis and overall survival (OS) in a cohort of newly diagnosed patients with MM. Methods: A total of 583 newly diagnosed MM patients were prospectively enrolled between 2010-2019 at the University of Chicago Medical Center. Epidemiology questionnaire and blood samples were collected at the time of diagnosis. We collected baseline clinical, laboratory, cytogenetic, and treatment data from electronic medical records. Vital status was ascertained using the National Death Index. Patients were followed through 31 December 2020 with an average follow-up length of 77.8 months. BMI was calculated using height and weight information collected from electronic health records and questionnaires. OS was defined as time from diagnosis until death from any cause. Chi-squared test and t-test were used to compare characteristics of patients by vital status. Hazard Ratios (HR) and 95% confidence intervals (CI) were derived from Cox proportional hazards models to examine the associations between BMI at different times and OS, adjusting for potential confounders. Stratified analyses were done to examine sex- and race-specific associations. Results: The median age at diagnosis was 63 years, 45% (n = 258) were female, and 27% (n = 150) were African Americans. Of the 572 MM patients, 176 (31%) deaths were identified during the follow-up. There was no significant association between elevated BMI at different time points (i.e., at diagnosis, 5 years before diagnosis, age 20, and maximum adulthood BMI) and OS after adjusting for age, race, sex, and prognostic variables (e.g., stage, serum lactate dehydrogenase levels). No association was found for both African Americans and European Americans. However, for women, obesity (BMI &gt; = 30) at the time of diagnosis was associated with a better OS (HR = 0.25; 95% CI = 0.12-0.54 for obese vs. normal weight) whereas in men, obesity at the time of diagnosis was associated with worse OS (HR = 2.54; 95% CI = 1.18-5.49). Conclusions: We found no association between BMI and OS in MM, irrespective of race. Our data showed that, compared to subjects with normal BMI at the time of diagnosis, female patients with elevated BMI had better survival, whereas a higher BMI was associated with inferior OS among male patients. Our findings of an effect modification by sex are novel and warrant further investigations. These findings might have clinical significance because BMI is amenable to lifestyle modification.
Enabling tandem repeat sequence genotype analysis across capture kits.
Authors: Shun H Yip, Michael Diamreyan, Edmund Wong, Raghuraman Ramamurthy, Sidney Tobias, Hao Cheng, Victor Solovyev, Cheuk Ying Tang
Journal: Journal of Clinical Oncology (2022)

e18700 Background: Previous studies on mutation calling have documented capture kit batch effects in Whole Exome Sequencing (WES) data from The Cancer Genome Atlas (TCGA) database, hindering direct comparison between samples from different capture kits. For example, in classification, a cancer type exclusively sampled by a specific capture kit in the training set would have very low accuracy if the testing set was sampled by another capture kit. To enable cross-capture-kit between-cancer genotype analyses with the TCGA dataset, a novel read count transformation algorithm is developed to remove capture kit batch effects. This algorithm was tested with our Machine Learning model which uses Tandem Repeat Sequence (TRS) mutation markers as training features. Methods: The proposed algorithm transforms TRS read count data to remove low quality samples, read depth differences, and capture kit batch effects from the dataset. Results: 1) TRS read count of WES samples are investigated. Particularly, we show that TRS site read counts do not correlate across capture kits but correlate within capture kits. This suggests that WES read count is largely independent from an exon’s location in the genome and is more strongly correlated with capture kit probes. 2) TRS detection rate for each sample within each capture kit is found to be normally distributed. Outliers with very low TRS detection rate can be used for quality filtering. 3) The transformation algorithm effectively removes capture kit batch effects from the dataset. At the same time, it retains cancer-specific signals in the samples. Before applying the transformation algorithm, cancer type classification accuracy is low (̃0-25%) if the testing data set uses a different capture kit from the training data set. We show that applying the transformation algorithm allows cancer type classification accuracy to improve by over 65%. Conclusions: We demonstrated that direct comparison of WES TRS read count data across capture kits is possible after application of our transformation algorithm. This opens the path to cross-capture-kit between-cancer genotype analyses with the TCGA dataset, which were previously unfeasible due to capture kit batch effects.
Dual-Tracer PET/CT-Targeted, mpMRI-Targeted, systematic biopsy, and combined biopsy for the diagnosis of prostate cancer
Authors: D. Qiu, J. Li, J. Zhang, C. Minfeng, X. Gao, Y. Tang, Y. Zhang, X. Yi, H. Yin, Y. Gan, G. Wang, X. Zu, S. Hu, C. Yi
Journal: European Urology (2022)
Sex Differences in Blood Pressure—A Measured Relook at Measures
Authors: Natalie A. Bello, Susan Cheng
Journal: JAMA Network Open (2022)

Yasmine Abbaoui; Catherine Fortier, PhD; Louis-Charles Desbiens, MD, MSc; Cédric Kowalski, MD; Florence Lamarche, MD, MSc; Annie-Claire Nadeau-Fredette, MD, MSc; François Madore, MD; Mohsen Agharazii, MD; Rémi Goupil, MD, MSc
Safety and tolerability of olaparib combined with breast radiotherapy in patients with triple-negative breast cancer: Final results of the RADIOPARP phase 1 trial.
Authors: Pierre Loap, Delphine Loirat, Frederique Berger, Manuel Rodrigues, Louis Bazire, Jean-Yves Pierga, Anne Vincent-Salomon, Fatima Laki, Latifa Boudali, Laurence Raizonville, Veronique Mosseri, Anne Jochem, Mamadou Diallo, Marc-Henri Stern, Alain Fourquet, Youlia M. Kirova
Journal: Journal of Clinical Oncology (2022)

534 Background: Preclinical studies have demonstrated that triple-negative breast cancer (TNBC) cells were sensitive to PARP inhibitors when used as radiosensitizers. Combining PARP-inhibitors with radiotherapy may consequently enhance the biological effectiveness of the irradiation, leading to improved locoregional control in TNBC patients. We aimed to establish the appropriate dosing and the safety profile of Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients with residual disease after neoadjuvant chemotherapy. Methods: RADIOPARP (NCT03109080) was a prospective phase I dose-escalation trial establishing the tolerance profile of Olaparib combined with breast radiotherapy in high-risk early TNBC patients. Inclusion criteria were resected TNBC with non-complete pathological response after neoadjuvant chemotherapy, or unresectable TNBC despite prior neoadjuvant chemotherapy. Olaparib was started seven days before irradiation and continued during radiotherapy. A time-to-event continual reassessment method was used to increase Olaparib through four increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day) with a 25% maximum probability rate of dose-limiting toxicities (DLT). Radiotherapy delivered 50 Gy to the breast or to the chest wall, with or without lymph node irradiation. Toxicities were graded according to CTCAE (version 4.03). Homologous recombination (HR) proficiency status was genetically determined based on shallow whole genome sequencing. Results: Twenty-four TNBC patients were enrolled between 09/2017 and 11/2019. Olaparib was escalated to 200 mg twice a day without DLT and the MTD was not reached. With a median follow-up of 34 months, no late treatment-related grade ≥ 3 toxicity was observed, and the maximum observed toxicities were limited to grade 2 breast pain (n=2), fibrosis (n=2), deformity (n=1) and telangiectasia (n=1). Three-year OS and EFS were 83% [95% CI: 70%-100%] and 65% [51%-91%], respectively. HR proficiency status was not associated with OS and EFS. Conclusions: Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients was well-tolerated. The MTD was not reached, and no significant late toxicity was reported. For future trials evaluating the anti-tumor efficacy of this combination, an Olaparib dose of 200 mg twice a day should be considered. Clinical trial information: NCT03109080.
GCT-05. Multi-institutional analysis of treatment modalities in metastatic germinoma in children
Authors: Margaret Shatara, Mohammad H Abu-Arja, Shannon MacDonald, Stephanie Reiners, Hamza Gorsi, Dinisha Govender, Hetal Dholaria, Sumanth Nagabushan, Jonathan Schwartz, Jen Chun Foo, Revathi Rajagopal, Stephanie Perkins, Ute Bartels, Mohamed S Zaghloul, Nada A Abdelhaleem, Moatasem El-ayadi, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors, with germinoma accounting for two-thirds of cases. Neoadjuvant chemotherapy with response-based reduced radiotherapy dose and field has become the standard management of localized CNS germinomas, however, treatment of primary metastatic disease has remained controversial. Furthermore, there is limited published research on the use of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS: We performed a retrospective multi-institutional data collection and analysis of patients diagnosed with metastatic germinoma since 2000 to assess the overall survival (OS) and event-free survival (EFS) of the different treatment modalities administered. RESULTS: We identified 78 patients with germinoma, in two tertiary care centers, of which nine patients (11.5%; eight males) had metastatic disease. The median age at presentation was 13.3 years. All patients had a biopsy at presentation confirming the diagnosis. Three patients had positive CSF cytology (M1). Six patients received craniospinal irradiation (CSI) with boost to primary and metastatic sites, of which five patients received total CSI dose of 24 Gy, while the dose was unknown for one patient. One patient required one cycle of chemotherapy prior to CSI due to worsening visual changes, which subsequently resolved. One patient received two cycles followed by whole ventricular irradiation (WVI) of 23.4 Gy with a boost to the primary bed. One patient received WVI without neoadjuvant chemotherapy. One patient developed anoxic brain injury and only received chemotherapy. He died of recurrent progressive disease 15 months post-diagnosis. The median follow-up time was 77.5 months (range 15-130.5 months), with an OS of 88.9%. Further multi-institutional data collection and analysis is underway and will be presented at the meeting. CONCLUSION: We anticipate our results may elucidate the role of neoadjuvant chemotherapy in the treatment of metastatic germinoma, and whether when combined with lower CSI doses did not compromise EFS/OS.
Management of Patients With Aggressive Nonmelanoma Skin Cancers
Authors: Valencia D. Thomas, Michael K. Wong, Andrew J. Bishop
Journal: Journal of the National Comprehensive Cancer Network (2022)

Nonmelanoma skin cancers (NMSCs), which encompass a variety of cutaneous malignancies, are frequently managed with surgery, radiation therapy, cytotoxic chemotherapy, systemic immunotherapy, and active surveillance. In this tumor board–style forum, a panel of experts used several case studies as a basis to review these approaches and to describe existing clinical challenges. The current NCCN Guidelines for NMSC, which reflect the most up-to-date, evidence-based data relating to the evaluation and management of NMSCs, also provide key considerations and recommendations for the treatment of this patient population.
Autologous CD19-directed CAR T cells produced by novel PrimeCARmanufacture platform exhibit safety, efficacy, and long persistence profiles in relapsed/refractory B-lineage acute leukemia (r/r B-ALL).
Authors: Shiqi Li, Zhi Yang, Zucong Chen, Yu Li, Lin Liu, Zhongtao Yuan, Yingzi Zhang, Le Luo, Lihua Fang, Yingnian Chen, Qianzhen Zhang, Junjie Shen, Yunyan Li, Linling Wang, Meiling Wang, Wei Zhu, Sanbin Wang, Cheng Qian
Journal: Journal of Clinical Oncology (2022)

7008 Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-ALL. However, the life-threatening side effects especially high grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) limited its wide application. To overcome these limitations, we established a novel PrimeCAR platform based on moderate activation and short expansion to manufacture MC-1-50, an autologous CD19-directed CAR T cell. Our preclinical study showed that MC-1-50 exerted a great efficacy and less cytokines secretion. Methods: In this Phase I /II study (NCT04271410), CAR T cells were manufactured by PrimeCAR platform, which reduces manufacture periods to about 2 days. T cells were transducted with a lentiviral vector encoding a humanized CD19 specific scFv following 4-1BB and CD3ζ cytoplasmic domain. Patients (pts) received single-dose of MC-1-50 at dose level 1 (1×10 5 CAR+/kg), level 2 (3×10 5 CAR+/kg), and level 3 (1×10 7 CAR+ totally, ranged 1.67-3.85×10 5 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m 2 ) and cyclophosphamide (200-300 mg/m 2 ) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Results: As of Feb 10, 2022, 13 pts with r/r B-ALL were infused with MC-1-50. Disease characteristics and outcomes are shown in the table. No DLTs were reported. Eleven pts (84%) experienced CRS, including 7 (54%) at grade 1 and 4 (30%) at grade 2, no ≥ 3 CRS were observed. One pts (7%) experienced grade 1 ICANS, no ≥ 2 ICANS occurred. The Tmax for IL-6 was detected around day 11 (123.3±165.16 pg/ml). There were similar low secretion features of other cytokines, which is consistent with low CRS and ICANS. In all dose levels, 13 pts finished 1M evaluation and the CR rate in 1M is 100%. Four pts finished 3M evaluation and the CR rate in 3M is 75%, 1 pts relapsed at the month 3 with CD19 mutation. One pts had a CR statue at the month 11. Cmax for CAR copy number in 3 dose levels are similar and the average number of Cmax of CAR is 275901.6 copies/ug genomic DNA. Conclusions: PrimeCAR platform could produce CAR T cells in very short time with high percentage of T scm . Treatment of r/r B-ALL at very low dose resulted in excellent safety profile, while exhibited a promising efficacy. That make this PrimeCAR platform potential for outpatient administration in the future. Clinical trial information: NCT04271410. [Table: see text]
Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time Window of Cardiomyocyte Proliferation and Myocardial Regeneration
Authors: Yuji Nakada, Yang Zhou, Wuming Gong, Eric Y. Zhang, Erik Skie, Thanh Nguyen, Yuhua Wei, Meng Zhao, Wangping Chen, Jiacheng Sun, S. Naqi Raza, Jake Y. Chen, Gregory P. Walcott, Daniel J. Garry, Jianyi (Jay) Zhang
Journal: Circulation (2022)
Focused ultrasound/microbubbles-assisted BBB opening enhances LNP-mediated mRNA delivery to brain
Authors: Koki Ogawa, Naoya Kato, Michiharu Yoshida, Takeshi Hiu, Takayuki Matsuo, Shusaku Mizukami, Daiki Omata, Ryo Suzuki, Kazuo Maruyama, Hidefumi Mukai, Shigeru Kawakami
Journal: Journal of Controlled Release (2022)
Discontinuation of imatinib in patients with oligo-metastatic gastrointestinal stromal tumor who are in complete radiological remission: A prospective multicenter phase II study.
Authors: Ivar Hompland, Kjetil Boye, Andri Papakonstantinou, Bård Røsok, Heikki Joensuu, Øyvind Bruland
Journal: Journal of Clinical Oncology (2022)

11535 Background: Life-long tyrosine kinase inhibitor (TKI) treatment is recommended for patients (pts) with metastatic GIST. We investigated whether highly selected pts with metastatic GIST may remain in durable complete remission after imatinib discontinuation. Methods: In this 1-group, prospective, multicenter phase II trial (NTC02924714) selected pts with overtly metastatic GIST discontinued imatinib treatment. Eligible pts had been treated with imatinib &gt; 5 yrs for oligo-metastatic (≤3 metastases) disease, had no GIST progression and had undergone either R0/R1 resection or radiofrequency ablation (RFA) of all metastases, and had no longer detectable metastases on CT/MRI imaging, The primary endpoint was 3-yr progression-free survival (PFS), overall survival was a secondary endpoint. We estimated to achieve an improvement from 15% to 35% in 3-yr PFS compared to pts treated in the BRF-14 trial with a sample size of 31 pts. Results: The trial closed early due to slow accrual. Between January 5, 2017, and June 5, 2019, 12 pts (males, 7) with a median age of 67 yrs (range, 50-85) were enrolled. All pts had their primary tumor surgically removed (stomach, 4; small bowel, 6; large bowel/rectum, 2). Seven pts had KIT exon 11 mutation, 2 KIT exon 9 mutation, 1 PDGFRA exon 12 mutation, 1 had no mutation in KIT/PDGFRA, and 1 pt had unknown GIST mutational status. Eight pts had liver metastases, 3 peritoneal metastases, and 1 had both. Prior to enrollment all pts were in macroscopic complete remission after surgical metastasectomy (n = 7), RFA (n = 2), or both (n = 1), and 1 pt achieved complete radiological response with imatinib. At enrollment, 8 pts had imatinib 400 mg/d and 4 had &lt; 400 mg/d. The median time of imatinib treatment before study entry was 8 yrs (range, 5-17). After imatinib discontinuation 7 (58%) pts progressed; the median time to progression was 10 mos (range, 2-31 mos). Five (42%) patients were progression-free after a median follow-up time of 42 mos (range, 30-59 mos). Median PFS was 23 mos and the estimated 3-year PFS 39%. Patients who progressed all achieved a second remission after restarting imatinib and were alive after a median follow-up time of 48 mos (range, 32 to 61 mos). Conclusions: The findings suggest that discontinuation of imatinib is safe in highly selected patients with oligo-metastatic GIST and that such patients may survive without detectable GIST progression for several years. The findings need to be viewed with caution due to the small pt numbers. Further study on imatinib discontinuation seem warranted. Clinical trial information: NCT02924714.
Determinants of Small for Gestational Age in Women With Type 2 Diabetes in Pregnancy: Who Should Receive Metformin?
Authors: Denice S. Feig, Bernard Zinman, Elizabeth Asztalos, Lois E. Donovan, Prakesh S. Shah, J. Johanna Sanchez, George Tomlinson, Kellie E. Murphy
Journal: Diabetes Care (2022)

In the MiTy (Metformin in Women With Type 2 Diabetes in Pregnancy) randomized trial of metformin versus placebo added to insulin, we found numerous benefits with metformin but identified an increased proportion of infants who were small for gestational age (SGA). We aimed to determine the predictors of SGA in order to individualize care.Using logistic regression, we assessed baseline maternal characteristics as predictors of SGA. We compared maternal/neonatal outcomes in SGA metformin and placebo groups using the t, χ2, or Fisher exact test, as appropriate.Among the 502 mothers, 460 infants were eligible for this study. There were 30 infants with SGA in the metformin group (12.9%) and 15 in the placebo group (6.6%) (P = 0.026). Among SGA infants, those in the metformin group were delivered significantly later than those in the placebo group (37.2 vs. 35.3 weeks; P = 0.038). In adjusted analyses, presence of a comorbidity (chronic hypertension and/or nephropathy) (odds ratio [OR] 3.05; 95% CI 1.58-5.81) and metformin use (OR 2.26; 95% CI 1.19-4.74) were predictive of SGA. The absolute risk of SGA was much higher in women receiving metformin with comorbidity compared with women receiving metformin without comorbidity (25.0% vs. 9.8%).In this study, we observed a high percentage of SGA births among women with type 2 diabetes and chronic hypertension and/or nephropathy who were treated with metformin. Therefore, with the aim of reducing SGA, it is reasonable to be cautious in our use of metformin in those with type 2 diabetes and chronic hypertension or nephropathy in pregnancy.
Sentinel node biopsy and regional recurrence following neoadjuvant chemotherapy in patients with isolated tumor cells: A rare event.
Authors: Alison Moody, Jaswinder Jutla, Alice P. Chung, Reva K Basho, Armando E. Giuliano
Journal: Journal of Clinical Oncology (2022)

e12581 Background: Lack of consensus exists regarding the optimal surgical axillary management of breast cancer patients treated with neoadjuvant therapy followed by sentinel node biopsy (SNB) with only isolated tumor cells (ITCs) identified in the sentinel node (SN). Few studies with limited patients have addressed this. A prospectively maintained database was reviewed to identify residual nodal metastatic burden and outcomes for patients with SN ITCs. Methods: Operable breast cancer patients treated with neoadjuvant therapy followed by breast surgery with SNB were identified who had only ITCs in the SN. Patients were excluded who had recurrent breast cancer, metastatic disease at time of operation, or who had an operation performed at another institution. Residual burden of axillary metastatic disease in patients who underwent completion axillary dissection and locoregional recurrence were examined. All SNs were examined with both hematoxylin and eosin stains as well as well as immunohistochemical stains. Results: 875 patients underwent neoadjuvant therapy followed by breast surgery and SNB from July 2007 to November 2021. Seventeen patients (1.9%) had only ITCs in the SN. The mean patient age of these 17 patients was 55.6 years (range 31-83 years). The majority had invasive ductal carcinoma (n = 15, 88.2%). Fourteen patients (82.4%) had ER+ tumors, 11 (64.7%) PR+ tumors, 2 patients (11.7%) had HER2+, and 3 patients (17.6%) had triple negative cancers. All patients had clinical T1 to T3 tumors and clinical N0 (n = 11, 64.7%), N1 (n = 5, 29.4%), or N2 (n = 1, 5.9%) disease. Two patients had isolated tumor cells identified on frozen section. Both of these patients underwent axillary dissection during the index operation and had further nodal disease identified (1 patient with ITCs only and 1 patient with macrometastasis). Fourteen patients had SN tumor free frozen sections but ultimately had ITCs identified with H&amp;E. Five of these patients underwent a completion axillary dissection. Three of the 5 patients (60%) had additional ITCs identified after completion ALND. Fourteen patients had nodal irradiation. The three patients who did not receive irradiation did not undergo ALND. All patients with ER+ tumors received adjuvant endocrine therapy, the 2 patients with HER2+ cancers received adjuvant targeted HER2 therapy, and 4 patients received adjuvant chemotherapy. At a mean follow-up of 21.8 months (range 2-63 months), no locoregional recurrences occurred in any patient. Conclusions: ITCs in the SN after neoadjuvant therapy is a rare finding and are unlikely to be associated with regional recurrence.